Abstract

Prostaglandin transporter Oatp2a1/Slco2a1 is expressed at the apical (AP) membranes of type-1 alveolar epithelial (AT1) cells. To investigate the role of OATP2A1 in PGE₂ handling by alveolar epithelium, we studied PGE₂ transport across and secretion from monolayers of rat AT1-like (AT1-L) cells obtained by trans-differentiation of type-2 alveolar epithelial cells (AT2) isolated from male Wistar rats. Rat AT1-L cells expressed Oatp2a1/Slco2a1, together with smaller amounts of Mrp4/Abcc4 and Oct1/Slc22a1. PGE₂ uptake was saturable with Km 43.9 ± 21.9 nM. Transcellular transport of PGE₂ across AT1-L cells grown on permeable filters in the AP-to-basolateral (BL) direction was 5-fold greater than that in the reverse direction, and was saturable with Km 118 ± 26.8 nM; it was significantly inhibited by OATP inhibitors, bromosulfophthalein (BSP) and suramin, and an MRP4 inhibitor, ceefourin-1. The effects of BSP on the distribution of PGE₂ produced by bradykinin-treated AT1-L cells and PGE₂-d₄ externally added on the AP side of the cells were simultaneously monitored. In the presence of BSP, PGE₂ increased more rapidly on the AP side, while PGE₂-d₄ decreased more slowly on the AP side. The decrease in PGE₂-d₄ from the AP side corresponded well to the increase on the BL side, indicating that intracellular metabolism did not occur. These results suggest that Oatp2a1 and Mrp4 mediate transepithelial transport of PGE₂ in the AP-to-BL direction. Therefore, OATP2A1 may be an important regulator of PGE₂ in alveolar epithelium by reducing secretion of PGE₂ and facilitating "re-secreting" PGE₂ present in the alveolar lumen to the interstitial space or blood.